Carlotta Gilardi


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Gilardi

First Name

Carlotta

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0000-0001-6373-3445

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2021 - 20256
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Publications 1 - 6 of 6
  • Stress-regulated miR-708-5p affects recognition memory and manic-like behavior through Neuronatin downregulation
    Item type: Doctoral Thesis
    Gilardi, Carlotta (2024)
    Mood disorders are a group of psychiatric illnesses that impact mood and cognition and are leading causes of disability and mortality. This category encompasses primarily Major Depressive Disorder (MDD) and Bipolar Disorder (BD). MDD involves prolonged depressive episodes, while BD is characterized by fluctuating mood states, ranging from depressive episodes to (hypo)manic phases. Mood disorders are highly heritable disorders, but their etiology and symptomatic outcome are also influenced by environmental stress factors, such as early life stressors. Recent studies have implicated microRNAs (miRNAs) in the pathophysiological mechanisms associated with mood disorders. The complex pathophysiological mechanisms of these disorders need further understanding to aid early diagnosis and effective pharmacotherapy. In this study, we showed that miR-708-5p, a microRNA previously linked to BD, is upregulated in the peripheral blood of psychiatrically healthy individuals at high risk of mood disorders due to genetic or environmental factors. miR-708-5p was also significantly upregulated in individuals diagnosed with BD. It holds promise, together with miR-499-5p, in distinguishing between BD patients, those with major depressive disorder (MDD), and healthy subjects. Furthermore, miR-708-5p was upregulated also in the hippocampus of juvenile rats that underwent early life stress, and of rats deficient for the cross-psychiatric risk-gene Cacna1c. Acute overexpression of miR-708-5p in the mouse hippocampus could recapitulate BD-associated behaviors, including antidepressant-like behavior, increased compulsivity, and memory impairments. miR-708-5p targets Neuronatin (Nnat), an endoplasmic reticulum localized protein which regulates intracellular calcium homeostasis. The simultaneous overexpression of miR-708-5p and Nnat in the mouse hippocampus rescued the BD-associated behaviors. Overall, our findings connect miR-708-5p-dependent regulation of Nnat to BD, offering new insights for diagnosing and treating the disorder.
  • The Ferret as a Model System for Neocortex Development and Evolution
    Item type: Review Article
    Gilardi, Carlotta; Kalebic, Nereo (2021)
    Frontiers in Cell and Developmental Biology
    The neocortex is the largest part of the cerebral cortex and a key structure involved in human behavior and cognition. Comparison of neocortex development across mammals reveals that the proliferative capacity of neural stem and progenitor cells and the length of the neurogenic period are essential for regulating neocortex size and complexity, which in turn are thought to be instrumental for the increased cognitive abilities in humans. The domesticated ferret, Mustela putorius furo, is an important animal model in neurodevelopment for its complex postnatal cortical folding, its long period of forebrain development and its accessibility to genetic manipulation in vivo. Here, we discuss the molecular, cellular, and histological features that make this small gyrencephalic carnivore a suitable animal model to study the physiological and pathological mechanisms for the development of an expanded neocortex. We particularly focus on the mechanisms of neural stem cell proliferation, neuronal differentiation, cortical folding, visual system development, and neurodevelopmental pathologies. We further discuss the technological advances that have enabled the genetic manipulation of the ferret in vivo. Finally, we compare the features of neocortex development in the ferret with those of other model organisms.
  • MicroRNA-138 controls hippocampal interneuron function and short-term memory in mice
    Item type: Journal Article
    Daswani, Reetu; Gilardi, Carlotta; Soutschek, Michael; et al. (2022)
    eLife
    The proper development and function of neuronal circuits rely on a tightly regulated balance between excitatory and inhibitory (E/I) synaptic transmission, and disrupting this balance can cause neurodevelopmental disorders, for example, schizophrenia. MicroRNA-dependent gene regulation in pyramidal neurons is important for excitatory synaptic function and cognition, but its role in inhibitory interneurons is poorly understood. Here, we identify miR138-5p as a regulator of short-term memory and inhibitory synaptic transmission in the mouse hippocampus. Sponge-mediated miR138-5p inactivation specifically in mouse parvalbumin (PV)-expressing interneurons impairs spatial recognition memory and enhances GABAergic synaptic input onto pyramidal neurons. Cellular and behavioral phenotypes associated with miR138-5p inactivation are paralleled by an upregulation of the schizophrenia (SCZ)-associated Erbb4, which we validated as a direct miR138-5p target gene. Our findings suggest that miR138-5p is a critical regulator of PV interneuron function in mice, with implications for cognition and SCZ. More generally, they provide evidence that microRNAs orchestrate neural circuit development by fine-tuning both excitatory and inhibitory synaptic transmission.
  • Bipolar-associated miR-499-5p controls neuroplasticity by downregulating the Cav1.2 subunit CACNB2
    Item type: Journal Article
    Martins, Helena C.; Gilardi, Carlotta; Sungur, A. Özge; et al. (2022)
    EMBO Reports
    Bipolar disorder (BD) is a chronic mood disorder characterized by manic and depressive episodes. Dysregulation of neuroplasticity and calcium homeostasis are frequently observed in BD patients, but the underlying molecular mechanisms are largely unknown. Here, we show that miR-499-5p regulates dendritogenesis and cognitive function by downregulating the BD risk gene CACNB2. miR-499-5p expression is increased in peripheral blood of BD patients, as well as in the hippocampus of rats which underwent juvenile social isolation. In rat hippocampal neurons, miR-499-5p impairs dendritogenesis and reduces surface expression and activity of the L-type calcium channel Cav1.2. We further identified CACNB2, which encodes a regulatory beta-subunit of Cav1.2, as a direct functional target of miR-499-5p in neurons. miR-499-5p overexpression in the hippocampus in vivo induces short-term memory impairments selectively in rats haploinsufficient for the Cav1.2 pore forming subunit Cacna1c. In humans, miR-499-5p expression is negatively associated with gray matter volumes of the left superior temporal gyrus, a region implicated in auditory and emotional processing. We propose that stress-induced miR-499-5p overexpression contributes to dendritic impairments, deregulated calcium homeostasis, and neurocognitive dysfunction in BD.
  • microRNA-218-5p coordinates scaling of excitatory and inhibitory synapses during homeostatic synaptic plasticity
    Item type: Journal Article
    Colameo, David; Maley, Sara M.; Winterer, Jochen; et al. (2025)
    Proceedings of the National Academy of Sciences of the United States of America
    Homeostatic synaptic plasticity (HSP) is a neuronal mechanism that allows networks to compensate for prolonged changes in activity by adjusting synaptic strength. This process is crucial for maintaining stable brain function and has been implicated in memory consolidation during sleep. While scaling of both excitatory and inhibitory synapses plays an important role during homeostatic synaptic plasticity, molecules coordinating these processes are unknown. In this study, we investigate the role of miR-218-5p as a regulator of inhibitory and excitatory synapses in the context of picrotoxin (PTX)-induced homeostatic synaptic downscaling (HSD) in rat hippocampal neurons. Using enrichment analysis of microRNA-binding sites in genes changing upon PTX-induced HSD, we bioinformatically predict and experimentally validate increased miR-218-5p activity upon PTX treatment. By electrophysiological recordings and confocal microscopy, we demonstrate that inhibiting miR-218-5p activity exerts a dual effect during HSD: It occludes the downscaling of excitatory synapses and dendritic spines, while at the same time attenuating inhibitory synapse upscaling. Furthermore, we identify the Neuroligin2 interacting molecule Mdga1 as a direct miR-218-5p target which potentially mediates the effect of miR-218-5p on homeostatic upscaling of inhibitory synapses. By performing long-term electroencephalographic recordings, we further reveal that local inhibition of miR-218-5p in the somatosensory cortex reduces local slow-wave activity during non-rapid-eye-movement sleep. In summary, this study uncovers miR-218-5p as a key player in coordinating inhibitory and excitatory synapses during homeostatic plasticity and sleep. Our findings contribute to a deeper understanding of how neural circuits maintain stability in the face of activity-induced perturbations, with implications for pathophysiology.
  • miR-708-5p is elevated in bipolar patients and can induce mood disorder-associated behavior in mice
    Item type: Journal Article
    Gilardi, Carlotta; Martins, Helena C.; Levone, Brunno R.; et al. (2025)
    EMBO Reports
    Mood disorders (MDs) are caused by an interplay of genetic and environmental (GxE) risk factors. However, molecular pathways engaged by GxE risk factors are poorly understood. Using small-RNA sequencing in peripheral blood mononuclear cells (PBMCs), we show that the bipolar disorder (BD)-associated microRNA miR-708-5p is upregulated in healthy human subjects with a high genetic or environmental predisposition for MDs. miR-708-5p is further upregulated in the hippocampus of rats which underwent juvenile social isolation, a model of early life stress. Hippocampal overexpression of miR-708-5p in adult male mice is sufficient to elicit MD-associated behavioral endophenotypes. We further show that miR-708-5p directly targets Neuronatin (Nnat), an endoplasmic reticulum protein. Restoring Nnat expression in the hippocampus of miR-708-5p-overexpressing mice rescues miR-708-5p-dependent behavioral phenotypes. Finally, miR-708-5p is upregulated in PBMCs from patients diagnosed with MD. Peripheral miR-708-5p expression allows to differentiate male BD patients from patients suffering from major depressive disorder (MDD). In summary, we describe a potential functional role for the miR-708-5p/Nnat pathway in MD etiology and identify miR-708-5p as a potential biomarker for the differential diagnosis of MDs.
Publications 1 - 6 of 6